Process for the preparation of spherical microparticles containing biologically active compounds

ABSTRACT

The invention relates to a process for encapsulating biologically active compounds in the form of substantially spherical microparticles, comprising the steps of 
     a) preparing an aqueous solution of surfactants, catalysts and monomers or prepolymers which are suitable for forming a crosslinked polycondensate, 
     b) forming an emulsion of the substantially water-insoluble biologically active compound or mixture thereof in the solution a) by adding said solution under high shear force, and 
     c) forming a solid capsule wall around the biologically active compound or mixture thereof by heating the reaction mixture to a temperature at which the crosslinking reaction tales place, 
     which process comprises fusing the biologically active compound or mixture thereof and adding the melt to the aqueous reaction mixture at a temperature which is higher than the temperature of the reaction mixture.

CONTINUING DATA

This application is filed under 35 USC 371 of PCT/EP95/02727, filed Jul.12, 1995.

The present invention relates to a process for the preparation ofspherical microparticles containing biologically active compounds byaddition of the preheated compound to the reaction solution. Theinvention also relates to the use of said microparticles for thepreparation of a composition for controlling plant pests, weeds oranimal parasites as well as to aqueous spray mixtures containing themicroparticles obtained in the practice of this invention.

The microencapsulation of active ingredients in polymeric materials withdifferent polymers is known and can be carried out by various methods,as described for example in Encyclopedia of Polymer Science, John WileySons, 1968, Vol. 8, pp. 719-736.

Particular demands are made of the release properties of biologicallyactive agrochemicals. The applied microparticles must, on the one hand,be comparably active in field application to e.g. emulsifiableconcentrates, and, on the the other, as small an amount as possibleshall be released on skin contact, so that a high degree of handlingsafety is ensured. Amino resins are of ten used as polymericencapsulating materials for microparticles that contain agrochemicalcompounds. An overview of the broad field of use of these resins formicroencapsulation is given, inter alia, in Acta Polymerica 40, (1989)No. 4, pp. 243-251.

The preparation and properties of microparticles prepared withself-crosslinking amino resins are described in Acta Polymerica 40,(1989) No. 5, pp. 325-331. In the processes referred to therein, thestarting materials are solid compounds which are e.g. additionallyground to give a fine dispersion in the aqueous polymer solution and arethen encapsulated. The drawback of this process is that the solidmaterials have to be ground to an average particle size of c. 10-30 μm.Depending on the crystal modification, the time investment and the lossof grinding stock may be considerable. The formation of unwanted andvery finely particulate dust constitutes a further problem in thisprocess, especially in lengthy grinding. The grinding process generallyresults in a broad granular distribution of the grinding stock rangingfrom very fine dust to fairly large particles. It is also known that theirregular shape of grinding stock particles requires a thick capsulewall for their complete encapsulation, thereby impairing the releaseproperties and often resulting in the formation of unwantedagglomerates.

EP-A-0,379,379 claims a composition and a process for the preparationthereof in which the microparticles are formed by coacervation of atleast two water-soluble polymers. The active ingredient is dissolvedtogether with a polymer in an organic solvent, the water-solublepolymers are dissolved in water, and both solutions are combined, withstirring. In a preferred composition, the active ingredient has amelting point below 80° C. and is added in the melt to the aqueoussolution at a temperature such that it remains in the molten state.Stable aqueous dispersions of microparticles are obtained. One drawbackof this process is that the claimed active ingredients must have lowmelting points.

EP-A-0,368,576 claims a process for encapsulating chlorpyrifos in aurea-formaldehyde or melamine-formaldehyde resin, wherein in particularthe high termite toxicity is also retained in the alkaline range--e.g.when applied to concrete--and the handling safety of these microcapsulesis greatly enhanced as compared with e.g. that of an emulsifiableconcentrate. Chlorpyrifos (melting point 42-43° C.) is fused and themelt is added to a polymer solution, while the temperature of thereaction medium (polymer solution) may not be below the melting point ofchlorpyrifos. The temperature is afterwards raised to 50° C. and thecationic urea-formaldehyde resin is crosslinked under acid conditions.The temperature of the fused chlorpyrifos is always below thetemperature of the reaction mixture. In this process too it is onlypossible to use low-melting active ingredients or melts at lowtemperature.

It has now been found that it is also possible to stir activeingredients having substantially higher melting points, or melts havingsubstantially higher temperatures, direct into the solution without thehigh temperature difference resulting in the formation of agglomeratesor in larger particle diameters. It is also not necessary for thetemperature of the reaction solution to be high when adding the activeingredient, so that this latter remains in the melt state. It hasfurther been found that the microparticles form particularly rapidly, asthe first polymer layer surrounding the particles undergoes a change intemperature via the crosslinking temperature and forms a first thinpolymer layer. The particles are therefore almost spherical andcompletely encapsulated by the polymer, even if only a minor amount ofpolymeric material is deposited. The dried microparticles form a readilyfree-flowing powder. Additional advantages result from the preparationof the microcapsules. For example, the excess heat resulting from thehigh temperature of the melt can be utilised to increase the temperatureof the aqueous polymer solution to the crosslinking temperature of thewall-forming material. The ensuing melt heat of the active ingredientscan further be utilised with particular advantage if the melting pointis above the temperature of the aqueous polymer solution.

The active ingredient encapsulated in the microparticles of thisinvention is released approximately uniformly over an extended period oftime from the microparticles, so that a good activity is achieved. Theresultant microparticle distribution is very narrow: typically ±5 μm ofthe average for 92% of all microparticles is achieved. The process isparticularly economic, as grinding can be dispensed with and the heatgenerated can be utilised for further process steps.

In one of its aspects, therefore, the invention relates to a process forencapsulating biologically active compounds in the form of substantiallyspherical microparticles, comprising the steps of

a) preparing an aqueous solution of surfactants, catalysts and monomersor prepolymers which are suitable for forming a crosslinkedpolycondensate,

b) forming an emulsion of the substantially water-insoluble biologicallyactive compound or mixture thereof in the solution a) by adding saidsolution under high shear force, and

c) forming a solid capsule wall around the biologically active compoundor mixture thereof by heating the reaction mixture to a temperature atwhich the crosslinking reaction takes place,

which process comprises fusing the biologically active compound ormixture thereof and adding the melt to the aqueous reaction mixture at atemperature which is higher than the temperature of the reactionmixture.

The spherical microparticles preferably have an average diameter of 0.5to 500 μm. More preferably the microparticles have an average diameterof 0.5 to 100 μm and, most preferably, of 0.5 to 20 μm.

The polycondensate is preferably 3 to 40% by weight, and thebiologically active compound is 97 to 60% by weight, of the total weightof the microparticles.

The precondensate is preferably an amino resin, most preferably apolycondensate of melamine and formaldehyde, a wholly or partiallyetherified melamine-formaldehyde condensate, a urea-formaldehydecondensate, a benzoguanamine-formaldehyde condensate, or a urea-glyoxalcondensate. Instead of formaldehyde, it is also possible to use otheraldehydes singly or in conjunction with formaldehyde.

The molar ratios of urea to formaldehyde are 1:2.5 to 1:3.5, preferably1:2.7 to 1:3.2.

The molar ratios of melamine to formaldehyde can be 1:3.5 to 1:8,preferably 1:4 to 1:6. The degree of etherification of these resins canbe adjusted by the molar ratio of melamine to methanol and is typicallyc. 1:10 to 1:20, preferably c. 1:15 to 1:18.

Suitable amino resins for forming microparticles will be found, interalia, in Kirk-Othmer, Encyclopedia of Chemical Technology, 3rd edition,Vol. 2, pp. 440-469.

The polycondensate is most preferably a melamine and formaldehydepolycondensate, a wholly or partially etherified melamine andformaldehyde polycondensate, or a urea-formaldehyde condensate.

The biologically active compound is preferably a pesticide or a mixtureof pesticides, and is most preferably a herbicide, an insecticide, anacaricide, a nematicide, an ectoparasiticide, a fungicide or a mixturethereof.

Typical examples of pesticides are: urea derivatives, triazines,triazoles, carbamates, phosphoric acid esters, dinitroanilines,morpholines, acylalanines, pyrethroids, benzilic acid esters andpolycyclic halogenated hydrocarbons.

Specific examples of pesticides suitable for use in the practice of thisinvention are listed hereinbelow (common names as given in The PesticideManual, 9th Edition, British Crop Protection Council):

Urea derivatives

Chlorbromuron, chloroxuron, chlorotoluron, fluometuron, thiazafluron andtriasulfuron.

Halogenated acetanilides

Dimethachlor, alachlor, propachlor.

s-Triazines

Atrazine, propazine, terbuthylazine, ametryn, aziprotryne, cyromazine.

Triazole derivatives

Etaconazole, 1- 2-(2,4-dichlorophenyl)-pent- 1 -yl!-1H-1,2,4-triazole,triadimefon, difenoconazole.

Carbamates

Dioxacarb, aldicarb, benomyl.

Phosphoric acid esters

Methidathion, anilofos, azinphos methyl, fenamiphos, azamethiphos.

Dinitroanilines

Benfluralin, pendimethalin, butralin, fluchloralin.

Acylalanines

Metalaxyl, fluralaxyl, benzoylprop ethyl, flamprop methyl.

Pyrethroids

Cypermethrin, resmethrin, tetramethrin.

Benzilic acid esters

Bromopropylates, chlorobenzilates, chloropropylates.

Miscellaneous

Bromoxynil, ioxynil, oxadiazon, dicofol, fenoxycarb.

Preferred pesticides are S-2,3-dihydro-5-methoxy-2-oxo-1,3,4thiadiazol-3-ylmethyl O,O-dimethyl phosphorodithioate (═methidathion)and 2-phenylamino-4-methyl-6-cyclopropylpyrimidine.

The temperature of the fused form or of the heated liquid form of thebiologically active compound or mixture thereof is above the temperatureof the aqueous solution. Preferably it is not less than 60° C. and, mostpreferably, 100° C., but may not exceed 200° C.

A preferred embodiment of the process is that wherein the differencebetween the temperature of the melt and the temperature of the aqueoussolution is 5 to 100° C.

The temperature range of the aqueous solution of the prepolymer ispreferably from 20 to 80° C., most preferably from 30 to 45° C.

The prepolymer is preferably used in a concentration of 5 to 50 g per100 g of water.

The aqueous solution may contain, in addition to the prepolymer, one ormore than one water-soluble oligomer or polymer as emulsifier ordispersant. The surfactants customarily used in formulation technologyare described, inter alia, in the following publications:

"McCutcheon's Detergents and Emulsifiers Annual", McPublishing Corp.,Glen Rock, N.J., USA, 1988,

H. Stache, "Tensid-Taschenbuch" (Handbook of Surfactants), 2nd edition,C. Hanser Verlag Munich, Vienna 1981,

M. and J. Ash. "Encyclopedia of Surfactants", Vol. I-III, ChemicalPublishing Co., New York, 1980-1981.

The surfactants are preferably nonionic surfactants such as polyethyleneglycols, polyethylene glycol monoalkyl ethers, polyethyleneglycol-polypropylene glycol copolymers.

Waxes may also be used as adjuvants. These may be natural waxes,modified natural waxes, or semi-synthetic or fully synthetic waxes. Itis preferred to use paraffin waxes. Conventional waxes are described,inter alia, in Ullmanns Enzyklopadie der technischen Chemie, 4th edition1983, Vol. 24, pp. 1-46. The waxes are preferably fused together withthe biologically active compound and the melt is then added to theaqueous reaction mixture.

Methods of producing high shear forces are known per se. It is preferredto use a high-speed impeller or a rotary homogeniser.

In another of its aspects, the invention relates to a process forcontrolling plant pests, weeds or animal parasites, which comprisessuspending the novel microparticles in a biologically activeconcentration in water and applying the suspension so obtained to thepests or to the locus thereof.

In yet another of its aspects, the invention relates to the use of thenovel microparticles for the preparation of a composition forcontrolling plant pests, weeds or animal parasites, and towater-dilutable powders, water-dispersible granules or aqueous spraymixtures containing said microparticles.

The invention is illustrated by the following Examples.

Examples for the preparation of the precondensates.

EXAMPLE A1

Preparation of a urea-formaldehyde precondensate

With stirring, 20 g (0.33 mol) of urea are dissolved in 100 g (1 mol) ofa 30% aqueous solution of formaldehyde. The pH is adjusted with 1Naqueous NaOH to 8.5-9.5 and the solution is then heated to a temperatureof 70° C. and further stirred slowly for 60 minutes at this temperature.The solution is afterwards cooled to room temperature.

EXAMPLE A2

Preparation of a modified melaimine-formaldehyde precondensate

With stirring, 28 g of melamine (0.22 mol) are added to 124 ml of a 30%aqueous solution of formaldehyde. The reaction mixture is adjusted with1N aqueous NaOH to pH 9 and heated to 94° C., whereupon the melaminedissolves while reacting with the aldehyde. The reaction mixture is thencooled to 62° C. and, after addition of 120 ml of methanol (3.75 mol)and 7 ml of a 15% aqueous solution of hydrochloric acid, the reaction iscarried out at 62° C. for 30 minutes. Then 2.8 g of triethanolamine areadded and the azeotropic mixture of methanol-water is distilled from thereaction mixture. After adjustment to a solids content of c. 40 to 60%by weight, 6 g of urea are added to the solution, which is then cooledto room temperature.

Example for the preparation of the microparticles.

EXAMPLE B1

120 ml of water and 24 g of the precondensate prepared according to

Example A2 as well as 3 g of polyethylene glycol (molecular weight 300)are charged to a reactor with temperature control. The reaction mixtureis heated to 60° C. and acidified with 12 ml of 2N aqueous citric acid.While stirring with a high-speed impeller of the Ultraturrax type at12,000 rpm, 50 g of fused2-phenylamino-4-methyl-6-cyclopropyl-pyrimidine are added and at atemperature of 85° C. After a reaction time of 10 minutes, stirring iscontinued with a paddle agitator at 500 rpm for 120 minutes at 60° C.,giving a suspension of fine particles having an average diameter of c.7.5 μm. The particles have a spherical form, are not agglomerated, andhave a narrow particle size distribution. The suspension can be furtherformulated direct in conventional manner or the particles can be driedto give a free-flowing powder.

EXAMPLE B2

The procedure of Example B1 is repeated, using the precondensate of

Example A1. After a reaction time of 5 minutes, acidification isadditionally effected with 6 ml of an aqueous 1N solution of HCl to givea suspension of fine particles having an average diameter of c. 7.5 μm.The particles have a spherical form, are not agglomerated, and have anarrow particle size distribution. The suspension can be furtherformulated direct in conventional manner or the particles can be driedto give a free-flowing powder.

EXAMPLE B3

60 ml of water and 3 g of the precondensate obtained according to

Example A2 as well as 0.15 ml of polyethylene glycol (molecular weight300) are charged to a reactor with temperature control. The reactionmixture is heated to 40° C. and then acidified with 2.1 ml of a 2Naqueous solution of citric acid. With stirring (Ultraturrax, 12 000rpm), 12.6 g of fused methidathion heated to 60° C. are added to thereaction mixture and the mixture is stirred for 10 minutes at thisspeed. Stirring is then continued at 60° C. with a propeller stirrer at500 rpm for 120 minutes. The batch is then cooled to give a suspensionof fine spherical particles having diameters of 1 to 10 μm.

EXAMPLE B4

The procedure described in Example B3 is repeated. A paraffin wax whichmelts at 100-120° C. is fused together with the methidathion and themelt is further heated to 150° C. The melt heated to this temperature isadded direct to the reaction solution and the procedure described inExample B3 is carried out to give a suspension of fine sphericalparticles having diameters of 1 to 10 μm.

What is claimed is:
 1. A process for encapsulating a biologically activecompound in the form of substantially spherical microparticles,comprising the steps ofa) preparing an aqueous solution of surfactants,catalysts and monomers or prepolymers which are suitable for forming acrosslinked polycondensate, b) forming an emulsion of the substantiallywater-insoluble biologically active compound or mixture thereof in thesolution a) by adding said solution under high shear force, and c)forming a solid capsule wall around the biologically active compound ormixture thereof by heating the reaction mixture to a temperature atwhich the crosslinking reaction takes place,which process comprisesfusing the biologically active compound or mixture thereof and addingthe melt to the aqueous reaction mixture at a temperature which ishigher than the temperature of the reaction mixture.
 2. A processaccording to claim 1, wherein the spherical microparticles have anaverage diameter of 0.5 to 500 μm.
 3. A process according to claim 1,wherein the spherical microparticles have an average diameter of 0.5 to100 μm.
 4. A process according to claim 1, wherein the sphericalmicroparticles have an average diameter of 0.5 to 20 μm.
 5. A processaccording to claim 1, wherein the polycondensate is 3 to 40% by weight,and the biologically active compound is 97 to 60% by weight, of thetotal weight of the microparticles.
 6. A process according to claim 1,wherein the precondensate is an amino resin.
 7. A process according toclaim 1, wherein the polycondensate is a melamine-formaldehydecondensate, a wholly or partially etherified urea-formaldehydecondensate, a benzoguanamine-formaldehyde condensate or a urea-glyoxalcondensate.
 8. A process according to claim 7, wherein thepolycondensate is a melamine-formaldehyde condensate, a wholly orpartially etherified melamine-formaldehyde condensate, or aurea-formaldehyde condensate.
 9. A process according to claim 1, whereinthe biologically active compound is a pesticide or a mixture ofpesticides.
 10. A process according to claim 9, wherein the biologicallyactive compound is a herbicide, an insecticide, an acaricide, anematicide, an ectoparasiticide, a fungicide or a mixture thereof.
 11. Aprocess according to claim 1, wherein the biologically active compoundis S-2,3-dihydro-5-methoxy-2-oxo-1,3,4 thiadiazol-3-ylmethylO,O-dimethyl phosphorodithioate (═methidathion) or2-phenylamino-4-methyl-6-cyclopropylpyrimidine.
 12. A process accordingto claim 1, wherein the temperature of the melt of the biologicallyactive compound or mixture thereof is above the temperature of theaqueous solution.
 13. A process according to claim 1, wherein thetemperature of the melt of the biologically active compound or mixturethereof is not less than 60° C.
 14. A process according to claim 1,wherein the temperature of the melt of the biologically active compoundor mixture thereof is not less than 100° C. and not higher than 200° C.15. A process according to claim 1, wherein the temperature of theaqueous solution containing the prepolymer is in the range from 40 to80° C.
 16. A process according to claim 1, wherein the temperature ofthe aqueous solution containing the prepolymer is in the range from 30to 45° C.
 17. A process according to claim 1, wherein the differencebetween the temperature of the melt and the temperature of the aqueoussolution is from 5 to 100° C.
 18. A process according to claim 1,wherein the prepolymer is used in a concentration of 5 to 50 g per 100 gof water.
 19. A process according to claim 1, which comprises fusing anatural wax, a modified natural wax, a semi-synthetic or fully syntheticwax together with the biologically active compound or mixture thereofand then adding this melt to the aqueous reaction mixture.
 20. A processaccording to claim 19, wherein the wax is a paraffin wax.
 21. A processaccording to claim 19, wherein the high shearing force is produced by ahigh-speed impeller.
 22. A process according to claim 19, wherein thehigh shearing force is produced by a rotary homogeniser.
 23. An aqueoussuspension comprising a pesticidally effective amount of themicroparticle product produced by the process of claim
 1. 24. A methodof controlling plant pests, weeds or animal parasites comprising thestep of applying the suspension of claim 23 to the plant pests, weeds oranimal parasites, or the locus thereof.